Glial fibrillary acidic protein
Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is abundantly expressed by astrocytes - a major population of glial cells in the central nervous system. GFAP is also expressed by ependymal cells, and is present in many peripheral tissues. [1] GFAP is a type III intermediate filament protein that maps, in humans, to 17q21.[2] It is closely related to vimentin, desmin, and peripherin, all of which are involved in the structure and function of the cell’s cytoskeleton.
Structure
Type III intermediate filaments have three domains, the most highly conserved of which is the rod domain. The rod domain coils around that of another filament to form a dimer, with the N-terminal and C-terminal of each filament aligned. Type III filaments such as GFAP can form both homodimers and heterodimers; GFAP can polymerize with other type III proteins or with neurofilament protein (NF-L).[3] GFAP and other type III IF proteins cannot assemble with keratins, the type I and II intermediate filaments. In cells that express both proteins, two separate intermediate filament networks form.
To form networks, the dimers combine to make staggered tetramers, which are the basic subunits of an intermediate filament. Since rods alone do not form filaments in vitro, it seems that the non-helical domains are needed for filament formation. The head and tail regions are more variable of sequence and structure. The head of GFAP contains two arginines and an aromatic residue that are needed for proper assembly. The sizes of the head and tail regions differ between GFAP and vimentin, which suggests that, when coassembled, they would align head-to-head rather than head-to-tail. This may enable more plastic functionality of the intermediate filament network.
Disease states
Glial scarring occurs in several neurodegenerative conditions, as well as after neural injury. The scar is formed by astrocytes interacting with fibrous tissue to re-establish the glia margins around the central tissue core [4] and is associated with up-regulation of GFAP expression. The scar acts as a barrier to neuronal growth, and thus suppresses neural regeneration.
Mutations in the GFAP gene can cause Alexander disease, a slowly progressing and fatal neurodegenerative disease. [5] This rare disorder mostly affects infants, with an onset during the first two years of life. Usually there are delays in mental and physical developmental, an abnormal increase in head size, and seizures. The less common juvenile form of the disease has an onset between the ages of two and thirteen, accompanied by excessive vomiting, difficulty in swallowing and speaking, poor coordination, and loss of motor control. Adult-onset is very rare, with symptomsthat sometimes mimic those of Parkinson’s disease or multiple sclerosis. The disease occurs in both males and females, and there are no ethnic, racial, geographic, or cultural/economic differences in its distribution.
More than 50 mutations of the GFAP gene have been identified as sporadic causes of Alexander disease. These changes alter the structure of GFAP, disrupting the formation of normal intermediate filaments. The abnormal GFAP accumulates in astroglial cells, contributing to the formation of Rosenthal fibers.
References
- ↑ Fuchs E, Weber K (1994). "Intermediate filaments: structure, dynamics, function, and disease". Ann Rev Biochem 63: 345–82. PMID 7979242.
- ↑ Bongcam-Rudloff E et al. (1991). "Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes". Cancer Res 51: 1553–60. PMID 1847665.
- ↑ Reeves SA et al. (1989). "Molecular cloning and primary structure of human glial fibrillary acidic protein". Proc Natl Acad Sci USA 86: 5178–82. PMID 2740350.
- ↑ Liedtke W et al. (1996). "GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination". Neuron 17: 607–15. PMID 8893019.
- ↑ J Rafael Gorospe Alexander Disease Bookshelf ID: NBK1172 PMID 20301351